The social and medical consequences of HIV infection of the central nervous system (CNS) are disability due to neurocognitive disorders, lowered quality of life, and decreased survival. Advances in the understanding of the pathogenesis and treatment of these disorders are vitally important. This research proposal outlines three integrated laboratory and clinical investigations that will examine the sources of CSF RNA, the potential role of the CNS as reservoir for HIV, and how monitoring cerebrospinal fluid (CSF) viral load may guide antiretroviral therapy for the CNS. The first study is an antiretroviral treatment trial designed to maximally diminish CSF viral load in patients with HIV-associated neurocognitive disorders (N = 45). This trial will test the hypothesis that improvement in neurocognitive function may be achieved through a reduction in CSF viral load. In a second study, previously untreated individuals with and without advanced immunosuppression (n=42), will be randomly assigned to CNS penetrating and nonpentrating antiretroviral combination therapies, and the dynamic change of CSF and plasma HIV RNA viral load will be determined serially. This study will test the hypothesis that in late stage disease, productive brain infection is the primary source of HIV in CSF, and that rational therapy requires CNS-penetrating antiretroviral drugs. Both studies will serially document plasma and CSF antiretroviral drug concentrations. A third study, drawing on antemortem and postmortem samples from 10 patients, will assess the phylogenetic relatedness of virus in various systemic and CNS compartments to confirm the hypothesis that as AIDS develops, the predominant HIV genetic variant in CSF resembles that in brain. Similar methodology, applied to CSF obtained from treatment trial participants, will assess the evolution of drug resistant mutations of HIV in the CNS. This research, which will provide groundwork for the rational diagnosis and treatment of HIV infection of the CNS, has a unique collaboration with the HIV Neurobehavioral Research Center for recruitment, neuromedical diagnosis, neuropsychological assessment, and acquisition of antemortem and postmortem samples.